Concert Genetic Testing: Prenatal Diagnosis (via Amniocentesis,
CVS, or PUBS) and Pregnancy Loss
V1.2025
Date of Last Revision: 11/2024
Revision log
Coding Implications

# CONCERT GENETIC TESTING:
# PRENATAL DIAGNOSIS (VIA
# AMNIOCENTESIS, CVS, OR PUBS)
# AND PREGNANCY LOSS

See [Important Reminder](#) at the end of this policy for important regulatory and legal
information.

## OVERVIEW

Prenatal diagnostic testing may be used to identify genetic conditions in fetuses at an increased
risk based on prenatal screening or for women who choose to undergo diagnostic testing due to
other risk factors, such as abnormal ultrasound findings, previous pregnancy with aneuploidy,
etc. Prenatal diagnostic testing for genetic disorders is performed on fetal cells derived from
amniotic fluid, and/or [percutaneous umbilical blood sampling (PUBS)](https://en.wikipedia.org/wiki/Amniocentesis) (cordocentesis) or from
placental cells via [chorionic villus sampling (CVS)](https://en.wikipedia.org/wiki/Chorionic_villus_sampling). Genetic testing techniques include
conventional chromosome analysis, chromosome fluorescence in situ hybridization (FISH),
chromosomal microarray analysis (CMA), targeted or Sanger sequencing, and next-generation
sequencing (NGS). Exome and genome sequencing are also emerging as new prenatal diagnostic
tools.

Genetic testing may also be used in an attempt to determine the cause of isolated or [recurrent
pregnancy loss](https://en.wikipedia.org/wiki/Recurrent_miscarriage), including miscarriages, intrauterine fetal demise (IUFD), and stillbirth. The
evaluation of both recurrent and isolated miscarriages and IUFD or stillbirth may involve genetic
testing of the products of conception (POC) and/or testing of fetal/placental cells from amniotic
fluid, CVS, or PUBS if available. Such testing of POC has typically been carried out through cell
culture and karyotyping of cells in metaphase. However, the analysis of fetal or placental tissue
has been inhibited by the following limitations: the need for fresh tissue, the potential for cell
culture failure, and the potential for maternal cell contamination. Potential benefits of identifying
a genetic abnormality in a miscarriage or IUFD include reducing emotional distress for families,

eliminating the need for additional testing to assess for causes of pregnancy loss, and assisting in
reproductive decision making for future pregnancies.

The decision to elect a prenatal diagnostic test and/or genetic testing following pregnancy loss
should be made jointly by the mother and/or parents and the treating clinician. Genetic
counseling, including facilitation of decision making, is strongly recommended.

In most cases, prenatal genetic testing for single gene disorders using molecular genetic testing
requires knowledge of the familial genetic variant which has been identified in a family member
(e.g., biological mother, biological father, and/or sibling).

## POLICY REFERENCE TABLE

### Coding Implications

This clinical policy references Current Procedural Terminology (CPT®). CPT is a registered
trademark of the American Medical Association. All CPT codes and descriptions are copyrighted
2023, American Medical Association. All rights reserved. CPT codes and CPT descriptions are
from the current manuals and those included herein are not intended to be all-inclusive and are
included for informational purposes only. Codes referenced in this clinical policy are for
informational purposes only. Inclusion or exclusion of any codes does not guarantee coverage.
Providers should reference the most up-to-date sources of professional coding guidance prior to
the submission of claims for reimbursement of covered services.

The tests,associated laboratories, CPT codes, and ICD codes contained within this document
serve only as examples to help users navigate claims and corresponding criteria; as such, they are
not comprehensive and are not a guarantee of coverage or non-coverage. Please see the Concert
Platform for a comprehensive list of registered tests.

| Criteria Sections | Example Tests (Labs) | Common CPT Codes | Common ICD Codes | Ref |
|-------------------|---------------------|-----------------|-----------------|-----|
| Chromosomal Microarray Analysis (CMA) for Prenatal Diagnosis | Reveal SNP Microarray - Prenatal (Integrated Genetics) | 81228, 81229, 81265, 88235 | O26.2, O28, Q00-Q99, Z14.8 | 3, 7 |
|                   | Prenatal Whole Genome Chromosomal Microarray (GeneDx) | 0469U |                 |     |
| Conventional Karyotype Analysis for Prenatal Diagnosis | IriSight CNV Analysis (Variantyx) | 88235, 88261, 88262, 88263, 88264, 88267, 88269, 88280, 88291 | O26.2, O28, Q00-Q99, Z14.8 | 7 |
|                   | Chromosome Analysis, Chorionic Villus Sample (Quest Diagnostics) | 88235, 88261, 88262, 88263, 88264, 88267, 88269, 88280, 88291 | O26.2, O28, Q00-Q99, Z14.8 | 7 |
|                   | Chromosome Analysis, Amniotic Fluid (Quest Diagnostics) | 88235, 88261, 88262, 88263, 88264, 88267, 88269, 88280, 88291 | O26.2, O28, Q00-Q99, Z14.8 | 7 |
| Chromosomal Microarray Analysis (CMA) for Pregnancy Loss | SNP Microarray-Products of Conception (POC)/Tissue (Reveal) (Labcorp) | 81228, 81229, 81265, 88235 | O03, Z37 | 1, 2, 9 |
|                   | Chromosomal Microarray, POC, ClariSure Oligo-SNP (Quest Diagnostics) | 81228, 81229, 81265, 88235 | O03, Z37 | 1, 2, 9 |
| Conventional Karyotype Analysis for Pregnancy Loss | Chromosome Analysis, POC, Tissue (Bioreference Labs) | 88235, 88261, 88262, 88263, 88264, 88267, 88269, 88280, 88291 | O03, Z37 | 1 |
|                   | Chromosome Analysis, Products of Conception (POC) (ARUP Laboratories) | 88235, 88261, 88262, 88263, 88264, 88267, 88269, 88280, 88291 | O03, Z37 | 1 |
| Prenatal Diagnosis for Noonan Spectrum Disorders/RASopathies | Prenatal Noonan Spectrum Disorders Panel (GeneDx) | 81404, 81405, 81406, 81407, 81479, 81442, 81265, 88235 | O28.3, O35.8XX0 | 6, 7, 8 |
|                   | Prenatal Noonan Syndrome (Integrated Genetics) | 81404, 81405, 81406, 81407, 81479, 81442, 81265, 88235 | O28.3, O35.8XX0 | 6, 7, 8 |
| Prenatal Diagnosis for Skeletal Dysplasias | Prenatal Skeletal Dysplasia Panel (GeneDx) | 81404, 81405, 81408, 81479, 81265, 88235 | O35.8XX0, O28.3 | 4, 11 |
|                   | Skeletal Dysplasia Core NGS Panel (Connective Tissue Gene Tests) | 81404, 81405, 81408, 81479, 81265, 88235 | O35.8XX0, O28.3 | 4, 11 |
| Prenatal Diagnosis via Exome Sequencing | XomeDx Prenatal - Comprehensive (GeneDx) | 81415, 81416, 81265, 88235 | O35.8XX0, O28.3 | 5, 12 |
|                   | Prenatal Exome Sequencing (Greenwood Genetic Center - Molecular Diagnostic Laboratory) | 81415, 81416, 81265, 88235 | O35.8XX0, O28.3 | 5, 12 |
| Prenatal Diagnosis via Genome Sequencing | Prenatal Whole Genome Sequencing | 81425, 81426, 81427, 88235, 81265 | O35.8XX0, O28.3 | 2, 10 |
|                   | IriSight Prenatal Analysis (Variantyx) | 0335U, 0336U |                 |     |

## OTHER RELATED POLICIES

This policy document provides criteria for prenatal or pregnancy loss diagnostic testing, and does
not address the use of conventional chromosome analysis, CMA, or FISH for preimplantation
genetic testing or the evaluation of suspected chromosome abnormalities in the postnatal period.
Please refer to:

*   Genetic Testing: Prenatal Cell-free DNA Testing for criteria related to prenatal cell-free
    DNA screening tests.
*   Genetic Testing: Prenatal and Preconception Carrier Screening for criteria related to
    carrier screening for genetic disorders.
*   Genetic Testing: Preimplantation Genetic Testing for criteria related to genetic testing of
    embryos prior to in vitro fertilization.
*   Genetic Testing: Multisystem Inherited Disorders, Intellectual Disability and
    Developmental Delay for criteria related to suspected chromosome abnormalities in the
    postnatal period.
*   Genetic Testing: General Approach to Genetic and Molecular Testing for criteria related
    to prenatal diagnostic or pregnancy loss genetic testing that is not specifically discussed in
    this or other non-general policies, including known familial variant testing.

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## CRITERIA

NOTE: This policy does not address the use of conventional chromosome analysis, CMA, and
FISH for preimplantation genetic testing or the evaluation of suspected chromosome
abnormalities in the postnatal period.

It is the policy of health plans affiliated with Centene Corporation® that the specific genetic
testing noted below is **medically necessary** when meeting the related criteria:



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NOTE: Current guidelines recommend that chromosome microarray analysis (CMA) be performed as the primary
test for patients undergoing prenatal diagnosis when the fetus has one or more major structural abnormalities
identified by ultrasound examination (see [Background and Rationale](#) for more information).

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## PRENATAL DIAGNOSIS VIA GENOME SEQUENCING

I. Prenatal diagnosis, via [amniocentesis, CVS, or PUBS](https://en.wikipedia.org/wiki/Amniocentesis), using genome sequencing (81425,
81426, 81427, 88235, 81265, 0335U, 0336U) is considered **investigational**.

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## DEFINITIONS

1. **Major malformations** are structural defects that have a significant effect on function or
    appearance. They may be lethal or associated with possible survival with severe or
    moderate immediate or long-term morbidity. Examples by organ system include:

    *   Genitourinary: renal agenesis (unilateral or bilateral), hypoplastic/cystic kidney
    *   Cardiovascular: complex heart malformations (such as pulmonary valve stenosis,
        tetralogy of fallot, transposition of the great arteries, coarctation of the aorta,
        hypoplastic left heart syndrome
    *   Musculoskeletal: osteochondrodysplasia/osteogenesis imperfecta, clubfoot,
        craniosynostosis, fetal growth restriction/intrauterine growth restriction (IUGR)
    *   Central nervous system: anencephaly, hydrocephalus, myelomeningocele
    *   Body wall: omphalocele/gastroschisis
    *   Respiratory: cystic adenomatoid lung malformation

2. **Amniocentesis** is a procedure in which a sample of amniotic fluid is removed from the
    uterus for prenatal diagnostic testing.

3. **Chorionic Villi Sampling (CVS)** is a procedure where a sample of chorionic villi is
    removed from the placenta for prenatal diagnostic testing.

4. **Percutaneous Umbilical Cord Blood Sampling (PUBS)** is a procedure where a sample
    of fetal blood is extracted from the vein in the umbilical cord.

5. **Recurrent pregnancy loss (RPL)** is defined as having two or more failed clinical
    pregnancies, including a current loss if applicable

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## BACKGROUND AND RATIONALE

### Chromosomal Microarray Analysis (CMA) for Prenatal Diagnosis

American College of Obstetricians and Gynecologists (ACOG)

An ACOG practice bulletin (#162, 2016, reaffirmed 2020) states the following:

*   Chromosomal aberrations that are smaller than the resolution of conventional karyotype
    also can result in phenotypic anomalies; these copy number variants can be detected in
    the fetus using chromosomal microarray analysis. When structural abnormalities are
    detected by prenatal ultrasound examination, chromosomal microarray will identify
    clinically significant chromosomal abnormalities in approximately 6% of the fetuses that
    have a normal karyotype. For this reason, chromosomal microarray analysis should be
    recommended as the primary test (replacing conventional karyotype) for patients
    undergoing prenatal diagnosis for the indication of a fetal structural abnormality detected
    by ultrasound examination. (p. e109)

*   Chromosomal microarray analysis has been found to detect a pathogenic (or likely
    pathogenic) copy number variant in approximately 1.7% of patients with a normal
    ultrasound examination and a normal karyotype, and it is recommended that
    chromosomal microarray analysis be made available to any patient choosing to undergo
    invasive diagnostic testing. (p. e.110)

ACOG practice bulletin #226 (2020) states the following regarding counseling patients: “Each
patient should be counseled in each pregnancy about options for testing for fetal chromosomal
abnormalities. It is important that obstetric care professionals be prepared to discuss not only the
risk of fetal chromosomal abnormalities but also the relative benefits and limitations of the
available screening and diagnostic tests.” (p. 859)

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Concert Genetic Testing: Prenatal Diagnosis (via Amniocentesis, CVS, or PUBS) and Pregnancy Loss

V1.2025
Date of Last Revision: 11/2024

CENTENE Corporation

Conventional Karyotype Analysis for Prenatal Diagnosis

American College of Obstetricians and Gynecologists (ACOG) and Society for Maternal Fetal Medicine (SMFM)

The ACOG and SMFM practice bulletin (#226, 2020) states the following:

“Prenatal genetic screening (serum screening with or without nuchal translucency [NT] ultrasound or cell-free DNA screening) and diagnostic testing (chorionic villus sampling [CVS] or amniocentesis) options should be discussed and offered to all pregnant women regardless of maternal age or risk of chromosomal abnormality.” (p. 862)

“Each patient should be counseled in each pregnancy about options for testing for fetal chromosomal abnormalities. It is important that obstetric care professionals be prepared to discuss not only the risk of fetal chromosomal abnormalities but also the relative benefits and limitations of the available screening and diagnostic tests.” (p. 859)

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Chromosomal Microarray Analysis (CMA) for Pregnancy Loss

American College of Obstetricians and Gynecologists (ACOG) and Society for Maternal Fetal Medicine (SMFM)

The ACOG and SMFM practice bulletin (#682) supports the following evaluation for pregnancy loss in their 2016 statement (reaffirmed 2020 and 2023):

"Chromosomal microarray analysis of fetal tissue (i.e., amniotic fluid, placenta, or products of conception) is recommended in the evaluation of intrauterine fetal death or stillbirth when further cytogenetic analysis is desired because of the test’s increased likelihood of obtaining results and improved detection of causative abnormalities." (p. e263)

American Society for Reproductive Medicine (ASRM)

The American Society for Reproductive Medicine (2012) issued an opinion on the evaluation and treatment of recurrent pregnancy loss. The statement drew multiple conclusions, one of which states: “Evaluation of recurrent pregnancy loss can proceed after 2 consecutive clinical pregnancy losses.” (p. 1108)

Papas and Kutteh (2021)

A review published in the Application of Clinical Genetics in 2021 by Papas and Kutteh recommends that genetic testing on products of conception should be performed after the second and subsequent pregnancy loss. Chromosome microarray is the preferred testing method. (p. 321)

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Conventional Karyotype Analysis for Pregnancy Loss

American Society for Reproductive Medicine (ASRM)

According to the ASRM’s 2012 statement, recurrent pregnancy loss (RPL) is defined as a distinct disorder defined by two or more failed clinical pregnancies. Evaluation of RPL can proceed after two consecutive clinical pregnancy losses, which may include karyotypic analysis of products of conception (p. 1103 and 1108) For the purposes of this committee, the ASRM defines clinical pregnancy as “…documented by ultrasonography or histopathological examination.” (p. 1103)

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Prenatal Diagnosis for Noonan Spectrum Disorders/RASopathies

Stuurman KE, Joosten M, van der Burgt I, et al, 2019

This cohort study of ultrasound findings of 424 fetuses in the Netherlands concluded with the recommendation for “testing of fetuses with solely an increased NT after chromosomal abnormalities have been excluded when the NT is greater than or equal to 5.0 mm. We also recommend testing when the NT is greater than or equal to 3.5 mm and at least one of the following anomalies is present: distended jugular lymph sacs (JLS), hydrops fetalis, polyhydramnios, pleural effusion and cardiac defects.” (p. 660)

“In general, an NGS panel of known rasopathy genes should be used when a rasopathy is suspected. Although we did not find pathogenic variants in every gene in the panel, in all genes, a prenatal phenotype has been documented in literature. Therefore, a smaller panel is not advisable. However, in countries where an extensive panel is not available, testing for only PTPN11 gene would catch at least 50% of the fetuses with a rasopathy.” (p. 661)

American College of Obstetricians and Gynecologists

The ACOG and SMFM practice bulletin (#226, 2020) defines an enlarged nuchal translucency (NT) as 3.0 mm or more or above the 99th percentile for the crown–rump length”. (p. e53)

GeneReviews: Noonan Syndrome

GeneReviews is an expert-authored review of current literature on a genetic disease, and goes through a rigorous editing and peer review process before being published online. The clinical summary for Noonan Syndrome gives the following prenatal features (Roberts, 2022):

• Polyhydramnios
• Lymphatic dysplasia including increased distended jugular lymphatic sacs, nuchal translucency, cystic hygroma, pleural effusion, and ascites
• Relative macrocephaly
• Cardiac and renal anomalies

The author points out that 3%-15% of chromosomally normal fetuses with increased nuchal translucency have PTPN11-associated Noonan syndrome.

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Prenatal Diagnosis for Skeletal Dysplasias

Krakow et al 2009

A guideline for prenatal diagnosis of fetal skeletal dysplasias (Krakow, Lachman, Rimoin, 2009) recommends the follow criteria:

• Fetuses with long bone measurements at or less than the 5th centile or greater than 3 SD below the mean should be evaluated in a center with expertise in the recognition of skeletal dysplasias. (p. 5)
• In addition, close attention should be paid to the shape and mineralization pattern of the fetal calvarium and fetal skeleton (poor or ectopic mineralization). Determining the elements of the skeleton that are abnormal, coupled with the findings of mineralization and shape of the bones can aid in diagnosis. (p. 3)

The guideline also lists several other common abnormal ultrasound findings in Table 2, including fractures of long bones (primarily femora), poor mineralization of the vertebrae, bent/bowed legs, and absent/hypoplastic scapula, as additional ultrasound findings that would prompt evaluation. (p. 10)

Scocchia, et al.

A 2021 study of the clinical utility of multigene panel testing for an unselected population of individuals with suspected skeletal dysplasia demonstrated a high diagnostic yield in prenatal cases. (p. 1)

A molecular diagnosis was established in 42% of patients (228/543). Diagnostic variants were identified in 71 genes, with variation in nearly half of these genes contributing to a molecular diagnosis for a single patient in this cohort. Overall, the most common genes in which molecular diagnoses were identified included: COL2A1 associated with type II collagenopathies; FGFR3 associated with achondroplasia, thanatophoric dysplasia, hypochondroplasia, and other conditions such as FGFR3-related craniosynostoses; and COL1A1 or COL1A2, associated with osteogenesis imperfecta. Together, these four genes accounted for over one third of all molecular diagnoses across the cohort. (p. 2-3)

Prenatal Diagnosis via Exome Sequencing

American College of Medical Genetics and Genomics (ACMG)

ACMG issued a statement on the use of fetal exome sequencing in prenatal diagnosis (2020) that included the following points to consider:

• “Exome sequencing may be considered for a fetus with ultrasound anomalies when standard CMA and karyotype analysis have failed to yield a definitive diagnosis. If a specific diagnosis is suspected, molecular testing for the suggested disorder (with single-gene test or gene panel) should be the initial test. At the present time, there are no data supporting the clinical use for ES for other reproductive indications, such as the identification of sonographic markers suggestive of aneuploidy or a history of recurrent unexplained pregnancy loss.” (p. 676)
• “Pretest counseling is ideally provided by a genetics professional during which the types of variants that may be returned in a laboratory report for all tested family members would be reviewed.” (p. 676)
• “With the use of prenatal ES, the turnaround time has to be rapid to maintain all aspects of reproductive choice. A rapid turnaround time has been demonstrated in the postnatal setting for critical genetic diagnoses in a pediatric and neonatal setting. Laboratories offering prenatal ES should have clearly defined turnaround times for this time-sensitive test.” (p. 677)
• “Post-test counseling is recommended, regardless of the test result. It should be provided by individuals with relevant expertise, preferably a genetics professional.” (p. 678)
• The statement also indicates that the detection rate of fetal anomalies is proportional to the severity of phenotype, with a range of 6% for fetuses with a single anomaly to 35% of fetuses with more than two anomalies. (p. 676)

Al-Koualty, et al 2022

“We performed a systematic literature review and meta-analysis focusing specifically on ES in cases of NIHF to determine the contribution of monogenic etiologies.” (p.504)

“In our meta-analysis, greater than one-third (37%) of cases of NIHF with negative clinical workup for anemia, infections, and chromosomal disorders have a monogenic disorder detectable by ES providing clarification of etiological category (e.g., syndromic, neuromuscular, metabolic, etc.) and inheritance pattern (e.g., autosomal dominant de novo, autosomal dominant inherited, autosomal recessive, or X-linked).” (p. 507)

“ES should be considered in the diagnostic workup of NIHF with and without associated ultrasound findings regardless of history of recurrence or consanguinity.” (p. 503-504)

Prenatal Diagnosis Via Genome Sequencing

American College of Obstetricians and Gynecologists (ACOG) and Society for Maternal Fetal Medicine (SMFM)

ACOG and SMFM (2016, reaffirmed in 2020 and 2023) issued a committee opinion No. 682, which included the following conclusions and recommendations for the use of chromosomal microarray testing and next-generation sequencing in prenatal diagnosis. Note that while whole exome sequencing is addressed in this opinion, whole genome sequencing is not yet recommended:

“Whole-exome sequencing also is a broad molecular diagnostic approach to identify the etiology for fetal abnormalities, and whole-exome sequencing of fetal DNA obtained by amniocentesis, chorionic villi, or umbilical cord blood is being offered on a research basis in some laboratories and for specific clinical indications in other laboratories. However, the routine use of whole-genome or whole-exome sequencing for prenatal diagnosis is not recommended outside of the context of clinical trials until sufficient peer-reviewed data and validation studies are published.” (p. 4)

Zhou J, et al. 2021

An article by Zhou, J, et al prospectively evaluated the clinical utility of whole genome sequencing (WGS) compared with standard chromosome microarray (CMA) in fetuses with structural anomalies. WGS was found to have a diagnostic rate of 19.8%, and was able to provide additional clinical information, such as a balanced translocation. “The article concludes by saying that “with a rapid TAT, good diagnostic yield, and less DNA required, WGS could be an alternative test in lieu of two separate analyses as it has an equivalent diagnostic yield to that of

CMA plus WES and provides comprehensive detection of various genomic variants in fetuses with structural or growth anomalies. However, more prospective studies with larger cohorts and further evaluation are warranted to demonstrate the value of WGS in prenatal diagnosis.” (p. 12)

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